Primary (AL) amyloidosis represents a protein folding disorder characterized by the pathologic deposition of mutated monoclonal light chains (LCs) that are associated with a plasma cell dyscrasia. LCs are deposited as extracellular aggregates, amyloid fibrils, in vital organs and tissues resulting in considerable morbidity and, eventually, death. The observation that amyloid fibrils are the hallmark of this and other amyloid associated diseases indicates that fibrils and/or its assembly intermediates are responsible for disease pathology. The disease state and prognosis for patients with AL amyloidosis are dictated by the pathogenic potential of the monoclonal LC, which has been attributed to mutation and germline gene usage. Therapy for patients with AL amyloidosis has been limited to reducing the synthesis of the amyloidogenic LC precursor by chemotherapy but, unfortunately, the disease process still progresses and the prognosis remains poor. Therefore, we propose a novel therapeutic strategy; namely, the identification of small molecules (SMs) that inhibit or prevent LC amyloid fibril growth by interfering with protein-protein interactions or by stabilizing the precursor protein. In this application, our goal is to identify 4 lead SMs that inhibit LC fibrillogenesis by determining inhibitory potencies and modes of action of a novel group of about 70 SMs. Fifty of these SMs are unique compounds, which we have identified from a preliminary screen of about 2000 structurally distinct compounds contained in the NCI's Diversity Set Library. The remaining approximately 20 SMs are FDA approved drugs with structural homology to these identified inhibitors. Each molecule will be tested for their capability to block LC fibril formation, irregardless of the kappa or lambda isotype or VL gene family. The ultimate goal is to identify the most efficacious compounds for Phase I Clinical Trials in patients with AL amyloidosis. Such agents may also prove to be of value in preventing other amyloid disorders, e.g., Alzheimer's disease and amyloid-like disorders associated with prion and Huntington's diseases. Lead small molecule inhibitors of immunoglobulin light chain amyloid fibril growth that we identify will constitute, in lieu of chemotherapy, a novel therapeutic approach for patients with primary (AL) amyloidosis. Furthermore, these molecules may be used for developing diagnostic reagents and as treatments for other amyloid and amyloid-like associated diseases, such as Alzheimer's and prion. [unreadable] [unreadable] [unreadable]